PMID- 19706758 OWN - NLM STAT- MEDLINE DCOM- 20091007 LR - 20220408 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 69 IP - 18 DP - 2009 Sep 15 TI - Genetic alterations in the phosphoinositide 3-kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycin. PG - 7311-9 LID - 10.1158/0008-5472.CAN-09-1077 [doi] AB - We investigated the genotype-dependent therapeutic potential of targeting the phosphoinositide 3-kinase (PI3K)/Akt pathway for thyroid cancer. Proliferation of TPC1, Hth7, FTC133, OCUT1, K1, and BCPAP cells that harbored PI3K/Akt-activating genetic alterations was potently inhibited by the Akt inhibitor perifosine, whereas SW1736, Hth74, WRO, KAT18, and TAD2 cells that harbored no genetic alterations had no or only modest responses. Inhibition of Akt phosphorylation by perifosine was seen in these cells. Genetic-dependent apoptosis was induced by perifosine in cells selectively tested. Similarly, potent inhibition of cell proliferation by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus occurred in virtually all the cells harboring genetic alterations, whereas modest inhibition was seen in some of the cells not harboring genetic alterations. Temsirolimus inhibited the phosphorylation of p70S6K, a substrate of mTOR. Knockdown of Akt1/2 or mTOR by shRNA approach inhibited the proliferation and colony formation of FTC133 and OCUT1 cells that harbored genetic alterations in the PI3K/Akt pathway but had no effect on SW1736 and KAT18 cells that did not. Transfection with PIK3CA mutants greatly sensitized SW1736 cells to perifosine and temsirolimus. Growth of xenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine. Thus, this work for the first time shows that genetic alterations in the PI3K/Akt pathway confer thyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR. This genotype-based targeting of the PI3K/Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for thyroid cancer and warrants further studies. FAU - Liu, Dingxie AU - Liu D AD - Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. FAU - Hou, Peng AU - Hou P FAU - Liu, Zhi AU - Liu Z FAU - Wu, Guojun AU - Wu G FAU - Xing, Mingzhao AU - Xing M LA - eng GR - R01 CA113507/CA/NCI NIH HHS/United States GR - R01 CA113507-03/CA/NCI NIH HHS/United States GR - R01 CA113507-01/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20090825 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (RNA, Small Interfering) RN - 107-73-3 (Phosphorylcholine) RN - 2GWV496552 (perifosine) RN - 624KN6GM2T (temsirolimus) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (PIK3CA protein, human) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM EIN - Cancer Res. 2009 Oct 15;69(20):8216 MH - Animals MH - Cell Growth Processes/drug effects MH - Cell Line, Tumor MH - Class I Phosphatidylinositol 3-Kinases MH - Humans MH - Mice MH - Mice, Nude MH - Oncogene Protein v-akt/antagonists & inhibitors/*genetics/metabolism MH - Phosphatidylinositol 3-Kinases/biosynthesis/*genetics/metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylcholine/*analogs & derivatives/pharmacology MH - Protein Kinases/*metabolism MH - RNA, Small Interfering/genetics MH - Signal Transduction/genetics MH - Sirolimus/*analogs & derivatives/pharmacology MH - TOR Serine-Threonine Kinases MH - Thyroid Neoplasms/*drug therapy/*enzymology/genetics/pathology MH - Transfection MH - Xenograft Model Antitumor Assays PMC - PMC2756336 MID - NIHMS133757 EDAT- 2009/08/27 09:00 MHDA- 2009/10/08 06:00 PMCR- 2010/09/15 CRDT- 2009/08/27 09:00 PHST- 2009/08/27 09:00 [entrez] PHST- 2009/08/27 09:00 [pubmed] PHST- 2009/10/08 06:00 [medline] PHST- 2010/09/15 00:00 [pmc-release] AID - 0008-5472.CAN-09-1077 [pii] AID - 10.1158/0008-5472.CAN-09-1077 [doi] PST - ppublish SO - Cancer Res. 2009 Sep 15;69(18):7311-9. doi: 10.1158/0008-5472.CAN-09-1077. Epub 2009 Aug 25.